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Shubha Tole couldn’t have asked for a better birthday present. Two doctoral students in the lab of the neurobiologist — who will turn 44 later this month — at the Tata Institute of Fundamental Research (TIFR) in Mumbai have unravelled a mechanism that has puzzled brain researchers for years. Anindita Sarkar and Lakshmi Subramanian have found the substance that gives the brain the signal to stop producing neurons and start forming glia cells.

Neurons are the brain cells that transmit information. Glia cells, which are far more numerous in the brain, supply nutrients to neurons and protect them from toxic attacks as well as maintain glucose levels in the brain.

The scientists studied the hippocampus — the region where learning happens and memories are formed — and found that a gene called Lhx2 has a critical role in deciding the number of neurons and glia cells. Interestingly, both types of cells are formed from the same stem cells. Scientists have known for a while that in a developing brain (in the embryo stage) the production of glia cells — particularly star-shaped astroglia cells that surround neurons to insulate and support them — commences only after the production of neurons stop. But they didn’t know what drives this switch.
Learning and memory are regulated by the hippocampus of the brain. Scientists have now found the molecule that decides how many neurons the hippocampus will have. T.V. Jayan reports

The findings, announced in a recent issue of the Proceedings of National Academy of Sciences journal, not only contribute significantly to the understanding of brain formation but also have clinical implications. It may help doctors understand the mechanisms underlying disorders like temporal lobe epilepsy (TLE) better, hopefully leading to better clinical intervention.

The TIFR scientists found that when they inactivated the Lhx2 gene in mice embryos, the production of neurons in the hippocampus stopped, triggering an early onset of astroglia production. And when the gene was kept active longer than normal, neuron production too continued longer than usual.

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“Our experiment has clearly demonstrated that the levels of Lhx2 decide the fate (of brain stem cells),” Tole told KnowHow. “It decides whether the glia-making pathway can be allowed to work or not.”

“This indicates the presence of a molecular timer that brings about the switch from neuron-making to glia-making,” says Aurnab Ghose, a neurobiologist at the Indian Institute of Science Education and Research (IISER) in Pune. This is an important step in understanding the regulation of timing in brain development.

According to Tole, striking the right balance between neurons and astroglia is critical. “If there are not enough neurons in the hippocampus, its function will be compromised,” the TIFR scientist says.

The mismatch between neurons and astroglia cells is implicated in TLE. “Loss of neuronal population (atrophy) and proliferation of astroglia in the hippocampus is the commonest pathology encountered in patients with drug-resistant TLE,” says K. Radhakrishnan, neurosurgeon and director of the Sri Chitra Tirunal Institute of Medical Sciences and Technology (SCTIMST) in Thiruvananthapuram. This means that TLE patients have too many glia cells in their hippocampus and keep losing neurons.

Such loss of neurons is found in nearly two-thirds of TLE patients. Though it was first described more than a century ago, it is not yet clear how this happens, says Radhakrishnan. It is presumed that febrile seizures occurring at a vulnerable period in early childhood in a person with a differently developed hippocampus results in the loss of neurons (hippocampus sclerosis).

The research provides an important insight into the factors that control the development of the hippocampus and at least one of the mechanisms that result in a differently developed hippocampus, the SCTIMST director says.

“How this information translates into human hippocampus sclerosis shall remain elusive till we learn more about the molecular genetic association of Lhx2 function/dysfunction in people with TLE,” says Radhakrishnan.

Significantly, switching on glia production in the hippocampus is not the only thing that Lhx2 does. Nearly three years ago Tole’s team, working jointly with their US counterparts, found that Lhx2 nudges brain stem cells to turn into the cerebral cortex. The cerebral cortex, which consists of the hippocampus and the neocortex, is involved in higher functions like language and complex thinking, apart from memory formation.

Interestingly, the TIFR scientists found that Lhx2 has no hold over the process of switching from neuron making to glia making in the neocortex. “We think that some other molecule may be doing that job,” says Tole.

“Lhx2 was already known to have a fundamental role in early brain development, required for the cortex to form in the first place instead of non-cortical structures. The current study uncovers an additional later role in development that is equally fundamental,” says Tole.

It is surprising that the same molecule has two really powerful roles to play. “It looks like a good example of evolutionary parsimony (one molecule having more than one critical function),” says Ghose.

Cancer stem cells constitute a small subfraction of tumor cells that are characterized by long lifespan and capacity for self-renewal, and are responsible for tumor development, resistance to treatments and cancer recurrence. In colon cancer, leptin is able to increase the growth, survival, and resistance to certain chemotherapy treatments in this key cell population.

Leptin, a fat tissue-derived pluripotent cytokine regulating appetite and energy balance in the brain, also controls many physiological and pathological processes in peripheral organs, including carcinogenesis.

Colon cancer has increased in developed countries, possibly due to sedentary lifestyles and high caloric diets. Prior research has linked obesity to colorectal cancer risk by .4-1.0 fold in men and up to 2.0 fold in premenopausal women.

“It is important to consider that cancer stem cells have been identified in several human malignancies,” says Monica Bartucci, study co-author. “Understanding how cancer stem cells interact with a tumor environment, including hormones like leptin, is likely to have significant implications for treatment management of different cancer types in human patients. We hope, in collaboration with Dr. Surmacz, not only to test the effects of leptin antagonist compounds on colon cancer stem cells but also to study the results of leptin stimulation on cancer stem cells isolated in other cancer tissues.”

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Rigorous physical exercise before binge drinking may reduce brain damage in adolescents.
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Monkeys are much like humans. If you leave them alone with alcohol, some of them are sure to get drunk quickly. But that’s a useful trait, because then you can study their brains easily. Scientists at the Scripps Research Institute near San Diego in the US did exactly that with adolescent monkeys, and came to some disturbing conclusions.

Chitra Mandyam and her colleagues at the Scripps Institute were investigating the effects of binge drinking among adolescents. They let the monkeys drink for an hour every day for 11 months. They then stopped the alcohol supply for two months, after which they examined the brains of the animals. The monkeys showed permanent damage in the hippocampus, an area that is crucial to the formation of new memory.

Adolescence — whether in rats, monkeys or humans — is a period of intense physical and mental change. “It is a vulnerable period,” says Mandyam.

According to several studies, binge drinking is increasing among adolescents. Over 60 per cent of these youngsters are at risk of developing brain disorders. It is thus necessary to understand how alcohol damages the brain, how lasting the damage is, and what can be done to reverse it.

“There have been several studies on rodents,” says Mandyam. “But this is the first time we studied binge drinking in monkeys.” There are many advantages of studying the phenomenon in monkeys. The animals are genetically similar to human beings, they drink like humans, and their brains are affected in a manner similar to that in humans.

Neurons in the hippocampus are generated the same way in monkeys as in humans. Since it is difficult to get the brains of adolescent humans for post-mortem, monkeys form the closest approximation for studying the effect of alcohol on adolescent humans.

Scientists at the Scripps Institute first selected a set of monkeys who liked to drink alcohol, and then divided it into two groups. One group was allowed to drink for 11 months and the other did not get to drink. Neurons in the hippocampus of the animals that drank had degenerated when seen even after two months of abstinence. The level of stem cells in the brain also decreased, suggesting the brain had less capacity to repair the damage.

The hippocampus is an important area of the brain that is involved in several functions like spatial memory formation, executive functioning and short-term and long-term memory formation. If damaged during adolescence, it could affect an individual’s functioning for a lifetime. This is particularly true if the stem cells are damaged. Mandyam’s study showed that as much as 90 per cent of the stem cells in the hippocampus could be damaged by binge drinking.

So the next question is: what can we do to reverse the damage? The brain is known to be very plastic, but can we invoke this plasticity when the stem cells in the hippocampus are damaged? There are no studies of monkeys, but those of rats suggest that one may be able to control this damage partly.

One particular study by Kimberly Nixon and her colleagues at the University of Kentucky in the US has shown that exercise before drinking may reduce the damage to a certain extent.

Nixon made rats exercise voluntarily for 14 days before four days of intense drinking. When the brains of the rodents were examined after that, they showed reduced damage compared with rats that did not exercise. However, we cannot necessarily conclude that all alcohol damage is reversible. “We do not know the threshold levels alcohol begins to be toxic,” says Nixon. “There is old data saying that over 50 per cent of alcoholics have persistent cognitive defects they never recover from.”

There may be several reasons why exercise shows reduced damage. It could be that the brain cells form new connections to compensate for lost cells. Abstinence and the passage of time may help the brain recover a bit. But we still do not know the many ways in which alcohol affects the brain.

However, we do know two things: binge drinking can permanently damage parts of the brain. And a period of exercise before drinking can prevent or at least reduce brain cell death.

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An hour and a half after feeding mice a single dose of epicatechin, animals that had ingested the compound suffered significantly less brain damage following an induced stroke.

Eurekalert reports:–
“While most treatments against stroke in humans have to be given within a two- to three-hour time window to be effective, epicatechin appeared to limit further neuronal damage when given to mice 3.5 hours after a stroke. Given six hours after a stroke, however, the compound offered no protection to brain cells.”